This program project grant proposal has as its primary goal the study of cellular and molecular events associated with the proliferation and differentiation of human hematopoietic cells. We propose to study in detail specific cellular events and biochemical processes in human erythroid, megakaryocytic, granulocytic and lymphoid cells in order to gain insight into the specific mechanisms that regulate or accompany the expression of a differentiated cellular phenotype. This work will be accomplished through a collaborative effort between established independent investigators in different departments of the University who will provide expertise in the different but interrelated disciplines that will be required for the success of the project: molecular biology, cell biology, cell proliferation, immunology, membrane biochemistry and membrane physiology. Specific projects that will be undertaken include: 1) studies of cell proliferation and biochemical characterization of normal and leukemic human erythropoietic stem cells, including studies of heme synthesis and membrane physiology in differentiating human erythroleukemia cells; 2) analysis of the control of human fetal globin gene expression; 3) studies of the regulation and expression of globin and specific nonglobin genes in differentiating human erythroid (K562), granulocytic (HL60) and lymphoid transformed cell lines; 4) isolation and characterization of genes for human histocompatibility antigens that are present on the surface of human lymphoid (and other) cells; and 5) studies of proliferation and differentiation of human megakaryocytic progenitor cells in an in vitro tissue culture system, including biochemical characterization of megakaryocytes. The scientific exchanges and interactions between separate investigators made possible by a program project grant would hopefully lead to a more rapid, substantial and efficient accrual of basic scientific knowledge than would otherwise be possible without a specific means for establishing and coordinating a wide-ranging multidisciplinary collaborative effort such as the one proposed in this application.